68 VLBW age <3 d receiving PN; birth wt: 500–1250 g; GA: 24–32 wk
Randomized double-blind
From d3 to d30 of life received premature formula (Similac Special Care Group) supplemented with Gln at 0.08 g/kg/d on d3 and reached 0.31 g/kg/d by d13, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
From d3 to d30 of life received premature formula (Similac Special Care Group) alone, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
(1) Hospital-acquired sepsis, tolerance to enteral feedings, and LOS in hospital; (2) analysis of T-cell subsets in peripheral blood during wk-4 of life, NEC, growth, respiratory status, and safety
(1) Reduced hospital-acquired sepsis (positive blood culture) when controlled for birth wt, fewer % d with no oral intake, and no differences in LOS in hospital; (2) blunted the rise in HLA-DR+ and CD16/CD56 subsets, no differences in NEC, wt, length, head circumference, mechanical ventilation or death, safe
68 VLBW age <3 d receiving PN; birth wt: 500–1250 g; GA: 25–32 wk
Randomized double-blind
From d3 to d30 of life received premature formula (Similac Special Care Group) supplemented with Gln at 0.08 g/kg/d on d3 and reached 0.31 g/kg/d by d13, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
From d3 to d30 of life received premature formula (Similac Special Care Group) alone, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
Plasma AA concentrations at 3 time points (prefeeding, transition to full feeds and full EN)
Decreased plasma concentrations of Ala, Gly, Ser, Thr, Phe, and total nonessential AA after ~2 wk supplementation (i.e., at transition to full EN), no differences between groups for plasma concentrations of Gln, Glu, or ammonia during study
11 VLBW age <3 d receiving PN; birth wt: <1250 g; GA: 24–32 wk
Randomized double-blind
Received premature formula (Similac Special Care Group) supplemented with Gln at 0.08 g/kg/d on d3 and increased to 0.2 g/kg/d on d10, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
Received premature formula (Similac Special Care Group) alone on d3 of life until d10, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
Whole body protein metabolism/Leu kinetics and Gln kinetics (IV infusions of L-[2H]Leu and L-[13C]Gln) on d10 of life in fed state, that is, during continuous EN (Gln supplemented or nonsupplemented) and PN
No differences in overall rate of appearance of Leu and Gln, no differences in Leu and Gln release from protein breakdown, no differences in Gln de novo synthesis or plasma Gln concentrations
68 VLBW age <3 d receiving PN; birth wt: 500–1250 g; GA: 24–32 wk
Randomized double-blind
From d3 to d30 of life received premature formula (Similac Special Care Group) supplemented with Gln at 0.08 g/kg/d on d3 and reached 0.31 g/kg/d by d13, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
From d3 to d30 of life received premature formula (Similac Special Care Group) alone, PN AA started at 0.5 g/kg/d on d3 until 3 g/kg/d by d8 ()
Hospital costs analysed by log-rank tests and Kaplan-Meier plots
Reduced median costs for hospitalisation, radiology, pharmacy, laboratory, and NICU, reduced median number of utilization units
25 LBW premature neonates age ≥14 d without acute illness and receiving exclusive EN; birth wt: 980–1890 g; GA: 27–35 wk
Randomized double-blind
Exclusive enteral preterm infant formula supplemented with Gln 0.7 g/kg/d (17% of total protein intake as Gln) for 21 d ()
Exclusive enteral preterm infant formula supplemented with isonitrogenous lactoserum extracted protein 0.7 g/kg/d (17% of total protein intake as lactoserum) for 21 d ()
Parameters of superior mesenteric blood flow velocities measured in fed state by pulsed Doppler ultrasound after 21 d supplementation
649 VLBW age <7 d receiving PN; birth wt: 500–1250 g
Multicentre randomized double-blind
Enteral Gln supplement (0.3 g/kg/d, 3% Gln in sterile water) given at the same time but separate from feedings for the first 28 d of life; AA intake ~3–3.5 g/kg/d by d7 ()
Enteral placebo (sterile water) given at the same time but separate from feedings for the first 28 d of life; AA intake ~3–3.5 g/kg/d by d7 ()
(1) Number of episodes of blood culture-proven nosocomial sepsis between 7 d to 36 wk of age; (2) suspected sepsis, pneumonia, UTI, meningitis, NEC, IVH, PVL, retinopathy of prematurity, use of oxygen at 36 wk, gastrointestinal dysfunction, growth, age and weight at discharge, and death
(1) No differences in nosocomial sepsis; (2) decreased gastrointestinal dysfunction and severe neurologic sequelae among survivors (Grades 3 and 4 IVH and PVL), no differences in suspected sepsis, pneumonia, UTI, meningitis, NEC, retinopathy of prematurity, use of oxygen at 36 wk, growth, age and wt at discharge, or death
26 LBW in good health and gaining wt aged 10–74 d (>23 d of age); birth wt: 693–1846 g; GA <32 wk
Randomized double-blind
Enteral Gln 0.6 g/kg/d for 5 d ()
(1) Enteral Gly 0.6 g/kg/d for 5 d () or (2) unsupplemented enteral formula for 5 d ()
Whole-body protein, Gln and urea kinetics on study d-6 (IV infusions of L-[1–13C,15N]Leu, [2H5]Phe, [15N2]urea, L-[5–15N]Gln) after 5 d supplementation during fasting (3 h after the last meal) and fed state, and plasma AA concentrations during fasting
Higher rate of urea synthesis, no differences in rates of appearance of Phe, Leu C or Leu N, no differences in rate of appearance of Gln or plasma Gln concentrations
69 VLBW premature neonates receiving PN; birth wt: <1500 g
Prospective intervention
From 8 d to 120 d of life received Gln supplement 0.15 g/kg/d BID mixed with sterile water and given at the same time but separate from feedings by an orogastric tube or orally ()
From 8 d to 120 d of life received sterile water (placebo) given at the same time but separate from feedings by an orogastric tube or orally ()
Growth parameters at birth, 1, 2, 3, and 4 mo and biochemical parameters at 4 mo
No differences in growth parameters at birth and 2 mo, higher wt, length, head circumference, MUAC and mid-thigh circumference at 3 and 4 mo, no toxicity signs
102 VLBW <48 h after birth receiving PN; birth wt: <1500 g; GA <32 wk
Randomized double-blind
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with Gln in increasing doses to ≤0.3 g/kg/d ()
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with isonitrogenous Ala in increasing doses to ≤0.3 g/kg/d ()
(1) Feeding tolerance; (2) growth, infectious morbidity, and short-term outcome
(1) No differences in time to full enteral feeding; (2) no differences in age PN discontinued, d of no enteral feeding, NEC or wt z-scores, decreased incidence of ≥1 serious infections (sepsis, meningitis, pyelonephritis, pneumonia, and arthritis), no differences in PDA treated with indomethacin or surgical ligation, mechanical ventilation, supplemental oxygen, retinopathy, age at discharge from NICU, age at discharge from hospital or death
86 VLBW <48 h after birth receiving PN; birth wt: <1500 g; GA <32 wk
Randomized double-blind
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with Gln in increasing doses to ≤0.3 g/kg/d ()
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with isonitrogenous Ala in increasing doses to ≤0.3 g/kg/d ()
Intestinal (faecal) microflora (bifidobacteria, lactobacilli, Escheria coli, streptococci, clostridia) at <48 h, at d7, d14, and d30 of life, as analysed by fluorescent in situ hybridization
No difference in prevalence of intestinal microflora
77 VLBW surviving infants at the corrected age of 1 y; birth wt: <1500 g; GA <32 wk
Followup of all surviving participants of a randomized double-blind study
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with Gln in increasing doses to ≤0.3 g/kg/d ()
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with isonitrogenous Ala in increasing doses to ≤0.3 g/kg/d ()
Incidence of allergic and infectious disease during the first year of life as assessed by validated questionnaires
Lower risk of atopic dermatitis, no differences in incidence of bronchial hyperactivity, infections of upper respiratory, lower respiratory, or gastrointestinal tracts
72 VLBW infants at the corrected age of 2 y; birth wt: <1500 g; GA <32 wk
Followup of participants of a randomized double-blind study
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with Gln in increasing doses to ≤0.3 g/kg/d ()
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with isonitrogenous Ala in increasing doses to ≤0.3 g/kg/d ()
Neurodevelopmental outcome (neurodevelopmental impairment, cerebral palsy, vision, hearing, MDI, and PDI of the Bayley Scale of Infant Development II) evaluated at the corrected age of 2 y
No differences in the incidence of an MDI nor a , no differences in the incidence of neurodevelopmental impairment or cerebral palsy
63 VLBW infants <48 h after birth receiving PN; birth wt: <1500 g; GA <32 wk
Randomized double-blind
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with Gln in increasing doses to ≤0.3 g/kg/d ()
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with isonitrogenous Ala in increasing doses to ≤0.3 g/kg/d ()
Th1 (IF-gamma, TNF-alpha, IL-2) and Th2 cytokine responses (IL-10, IL-5, IL-4) at 48 h, d7, and d14 of life following in vitro whole blood cell stimulation as analyzed by cytometric bead array
76 VLBW infants at 6 y of age; birth wt: <1500 g; GA <32 wk
Followup of participants of a randomized double-blind study
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with Gln in increasing doses to ≤0.3 g/kg/d ()
From 3 d to 30 d of life received enteral preterm formula or breast milk supplemented with isonitrogenous Ala in increasing doses to ≤0.3 g/kg/d ()
Allergic (atopic dermatitis, hay fever, recurrent wheeze, and asthma) and infectious disease (upper and lower respiratory tract infection, gastrointestinal tract infection, urinary tract infection) at 6 y of age as assessed by validated questionnaires
Decreased risk of atopic dermatitis, no differences in hay fever, recurrent wheeze or asthma, decreased risk of gastrointestinal tract infection, no differences in upper or lower respiratory tract infection or urinary tract infection
VLBW: very low birth weight; PN: parenteral nutrition; wt: weight; GA: gestational age; AA: amino acid; EN: enteral nutrition; IV: intravenous; LOS: length of stay; NEC: necrotizing enterocolitis; ICU: intensive care unit; LBW: low birth weight; UTI: urinary tract infection; IVH: intraventricular hemorrhage; PVL: periventricular leukomalacia; PDA: patent ductus arteriosus; NICU: neonatal intensive care unit; BID: twice a day; MUAC: mid upper arm circumference; MDI: Mental Developmental Index; PDI: Psychomotor Developmental Index; Th1: T helper type 1; Th2: T helper type 2; IF: interferon; TNF: tumor necrosis factor; IL: interleukin.
*, **Originating from the same cohort.
